1. Field of the Invention
The present invention is broadly directed to a class of thiazolidinone and metathiazanone compounds and their derivatives useful as potassium channel inhibitors.
2. Description of Related Art
Potassium channels are expressed in eukaryotic and procaryotic cells, and are elements in the control of electrical and nonelectrical cellular functions. Subclasses of these channels have been named based on amino acid sequence and functional properties, and include for example voltage gated potassium channels (e.g., Kv1, Kv2, Kv3, Kv4). Subtypes within these subclasses have been characterized as to their putative function, pharmacology and distribution in cells and tissues (Chandy and Gutman, "Voltage-gated potassium channel genes" in Handbook of Receptors and Channels-Ligand and Voltage-gated Ion Channels, ed. R. A. North, 1995; Doupnik et al., Curr. Opin. Neurobio. 5:268, 1995).
Inhibitors of potassium channels lead to a decrease in potassium ion movement across cell membranes. Consequently, such inhibitors induce prolongation of the electrical action potential or membrane potential depolarization in cells containing the inhibited or blocked potassium channels. Prolonging of the electrical action potential is a preferred mechanism for treating certain diseases, e.g., cardiac arrhythmias (Colatsky et al., Circulation 82:2235, 1990). Membrane potential depolarization is a preferred mechanism for the treating of certain other diseases, such as those involving the immune system (Kaczorowski and Koo, Perspectives in Drug Discovery and Design, 2:233, 1994).
Potassium channels which exhibit functional, pharmacological and tissue distribution characteristics have been cloned. These cloned potassium channels are useful targets in assays for identifying candidate compounds for the treatment of various disease states. For example, the delayed rectifier voltage-gated potassium channel termed I.sub.kur or I.sub.SUS which has been reported to contain the Kv1.5 .alpha.-subunit gene product is generally believed to be important in the repolarization of the human atrial action potential and thus is a candidate potassium channel target for the treatment of cardiac arrhythmias especially those occurring in the atria (Wang et al., Circ. Res. 73:1061, 1993; Fedida et al., Circ. Res. 73:210, 1993; Wang et al., J Pharmacol. Exp. Ther. 272:184, 1995; Amos et al., J Physiol., 491:31, 1996).
The present invention is related to thiazolidinone and metathiazanone compounds which have been found to be useful as inhibitors of potassium channel function. Such compounds have been found to be especially active as inhibitors of voltage-gated potassium channels and may therefore be utilized for the treatment of diseases, conditions and disorders in which prolongation of cellular action potentials or the induction of cell membrane depolarization would be beneficial. These disease states, conditions and disorders include, but are not limited to cardiac arrhythmias, cell proliferative disorders including cancer, disorders of the auditory system, central nervous system mediated motor dysfunction and disorders of pulmonary, vascular and visceral smooth muscle contractility.
It is an object of the present invention, therefore, to provide a method of treating diseases, conditions and disorders in mammals, including humans, which respond to the inhibition of potassium channel function, which method comprises administering to a mammal in need thereof certain thiazolidinone or metathiazanone compounds.
Another object of the invention is to provide certain thiazolidinone and metathiazanone compounds which are useful for the treatment of such diseases, conditions and disorders in mammals, including humans.